In search of triallelism in Bardet–Biedl syndrome

Abstract

Bardet-Biedl syndrome (BBS) is a model disease for ciliopathy in humans. The remarkable genetic heterogeneity that characterizes this disease is consistent with accumulating data on the interaction between the proteins encoded by the 14 BBS genes identified to date. Previous reports suggested that such interaction may also extend to instances of oligogenic inheritance in the form of triallelism which defies the long held view of BBS as an autosomal recessive disease. In order to investigate the magnitude of triallelism in BBS, we conducted a comprehensive analysis of all 14 BBS genes as well as the CCDC28B-modifier gene in a cohort of 29 BBS families, most of which are multiplex. Two in trans mutations in a BBS gene were identified in each of these families for a total of 20 mutations including 12 that are novel. In no instance did we observe two mutations in unaffected members of a given family, or observe the presence of a third allele that convincingly acted as a modifier of penetrance and supported the triallelic model of BBS. In addition to presenting a comprehensive genotype/phenotype overview of a large set of BBS mutations, including the occurrence of nonsyndromic retinitis pigmentosa in a family with a novel BBS9 mutation, our study argues in favor of straightforward autosomal recessive BBS in most cases.

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

“…Furthermore, the success we have had in combining autozygome and exome analysis in delineating the genetic architecture of other genetically heterogeneous disorders, for example, Osteogenesis imperfecta, retinal dystrophy, cataract, mitochondrial diseases, Bardet-Biedl syndrome, and Joubert syndrome 26,[28][29][30][31] 33 ), encouraged us to use a similar approach on MKS to not only determine the mutation distribution in known MKS disease genes but to also potentially identify novel candidate disease genes.…”

Bardet-Biedl Syndrome

“…Disruption of the cilia leads to abnormalities of sensory perception. About 1/4 th of all cases of BBS result from mutations in the BBS1 gene 3 ; 20% of cases are because of mutations in the BBS10 gene. 2,3,4 In about 25% of people with Bardet-Biedl syndrome, the cause of the disorder is unknown.…”

“…About 1/4 th of all cases of BBS result from mutations in the BBS1 gene 3 ; 20% of cases are because of mutations in the BBS10 gene. 2,3,4 In about 25% of people with Bardet-Biedl syndrome, the cause of the disorder is unknown. 5 ,, Figure 1 We are presenting here a case of BBS, which is rarely encountered in clinical practise -BBS with a normal genotype.…”

Human Genetics and Clinical Aspects of Neurodevelopmental Disorders

“…a third allele, which they speculate is necessary and perhaps sufficient for expression of any symptoms of the disease [87][88][89]. However, this model has been challenged by others [90][91][92][93][94], and at least one group maintains that all individuals that they have studied with two autosomal recessive mutations have 100% 'penetrance', but with variable expression, i.e. one individual might only have retinitis pigmentosa whereas another individual might have the full-blown symptoms of BardetBiedl syndrome [90].…”

“…However, this model has been challenged by others [90][91][92][93][94], and at least one group maintains that all individuals that they have studied with two autosomal recessive mutations have 100% 'penetrance', but with variable expression, i.e. one individual might only have retinitis pigmentosa whereas another individual might have the full-blown symptoms of BardetBiedl syndrome [90]. One wonders whether the debate about triallelism, with this idea of 0% 'penetrance' in the absence of a third allele, might really just be a semantic one due to problems with the phenotyping of 'unaffected' individuals, particularly if these individuals were not evaluated longitudinally.…”